Project 2: Targeted therapies for T cell acute lymphoblastic leukemia (T-ALL)
The long-term goal of this project is to develop novel targeted therapies for T-cell acute lymphoblastic leukemia (T-ALL). T-ALL is an aggressive hematologic malignancy that comprises 15% of pediatric ALL and 25% of adult-ALL. Current treatment consists of intense chemotherapy that is associated with acute and chronic life-threatening or debilitating toxicities. Five-year event-free survival is 70-75% for children, 30-40% for adults under 60, and less than 10% for adults over age 60. The prognosis after relapse is dismal, with 3-year event-free survival of only 10-15%. There is compelling evidence that increased MYC activity is central to the pathogenesis of most cases of T-ALL. Although MYC is a potent oncogene, it has an Achilles heel. In addition to providing a proliferative signal, MYC strongly induces apoptosis, in part, through an ARF/MDM2/TP53 pathway. In T-ALL this negative feedback loop is disrupted due to inactivating mutations of CDKN2A (encoding ARF). This project will explore the hypothesis that T-cell acute lymphoblastic leukemia (T-ALL) will be sensitive to drugs that interfere with MYC-survival signaling. This project includes a clinical trial of a novel CXCR4 antagonist (BL-8040) in combination with chemotherapy to treat patients with relapsed/refractory T-ALL.